The World Health Organization projects diabetes to be the 7th leading cause of death in 2030, with one in every ten adults (more than 500 million people) expected to have the condition. Current diabetic therapies have a market of at least $35 billion (US) and the value is predicted to rise steeply due to changes in lifestyle and increasing prevalence of diabetes. The size and rapid growth of this market make it one of the largest sectors in global healthcare.
Recombinant human insulin is the mainstay of the diabetes drug market. Standard pharmaceutical preparations of recombinant human insulin contain zinc ions along with a phenolic preservative. The addition of zinc ions stabilizes the protein formulation by inducing the formation of an insulin hexamer. However, a delay in activity is observed despite the soluble state of insulin in these formulations. This delay has been associated with the time required for the hexamer to dissociate into the active monomeric state before it is absorbed from the interstitium. Thus, decreasing the propensity of insulin to self-associate while maintaining long-term stability could minimize the lag time before onset of activity following insulin administration.
Significant research investment has been dedicated to engineering insulin analogs with improved therapeutic properties, including longer duration of action, increased efficacy and increased speed of action. Extensive biophysical characterization of the aggregation of native insulin has made it possible to engineer insulin analogs with improved therapeutic profiles. These include rapid-acting insulin lispro (Humalog®, Eli Lilly), in which the positions of Lys29 and Pro28 in the insulin B-chain are switched, and insulin aspart (Novalog®, Novo Nordisk), in which Pro28 is replaced by aspartate. Additionally, insulin glulisine (Apidra®, Sanofi-Aventis) comprises a substitution of Asn3 in the insulin B-chain with Lysine and a substitution of Lys29 in the B-chain with glutamate. Nevertheless, additional engineering of insulin analogs may further improve its therapeutic profile.